Substituted n-heteroaryl-1, 2-diaminocyclobutene-3, 3-diones

ABSTRACT

The compounds of the formula:    &lt;IMAGE&gt;  (I)  wherein: R1 and R2 are, independently, hydrogen, straight or branched chain alkyl or mono- or bi-cyclic alkyl; A is quinoline group which may be substituted by alkyl, perfluoroalkyl, alkoxy, perfluoroalkoxy, amino, alkylamino, dialkylamino, alkylsulfonamido, alkylcarboxamido, nitro, cyano or carboxyl; or a pharmaceutically acceptable salt thereof, are smooth muscle relaxants.

This is a division of application Ser. No. 08/153,706 filed Nov. 17,1993, now U.S. Pat. 5,354,763.

BACKGROUND OF INVENTION

The present invention relates to novel 1, 2-diamino derivatives ofcyclobutene 3,4-diones having pharmacological activity, to a process fortheir preparation, to pharmaceutical compositions containing them, andto their use in the treatment of disorders associated with smooth musclecontraction; via potassium channel modulation. Such disorders include,but are not limited to: urinary incontinence, hypertension, asthma,premature labor, irritable bowel syndrome, congestive heart failure,angina, and cerebral vascular disease.

Stemp et al. disclose a class of amino substituted cyclobutenedionederivatives of chromans described as having blood pressure loweringactivity and bronchodilatory activity in EP-426379-A2. Several series of1-amino-2-phenylalkylamino-cyclobutene-3,4-diones are reported as H-2receptor antagonists by Algieri et al. in U.S. Pat. No. 4,390,701.Several related 1-amino-2-phenoxyalkylamino derivatives are disclosed byNohara et al. in U.S. Pat. No. 4,673,747.

The syntheses of variously substituted1,2-diamino-cyclobutene-3,4-diones are described in the followingpublications: Tietze et al., Chem Ber. 1991, 124, 1215; Tietze et al.,Bioconjugate Chem. 1991, 2, 148; Ehrhardt et al., Chem. Ber. 1977, 110,2506, and Neuse et al., Liebigs Ann. Chem. 1973, 619.

DESCRIPTION OF THE INVENTION

Accordingly, the present invention discloses compounds represented bythe formula (I): ##STR2## wherein: R₁ and R₂ are, independent from eachother, hydrogen, C₁₋₁₀ straight chain alkyl, C₁₋₁₀ branched alkyl, orC₃₋₁₀ cyclic or bicyclic alkyl;

A is selected from the group consisting of: ##STR3## wherein: R₁ R₂ are,independent from each other, hydrogen, C₁₋₁₀ straight chain alkyl, C₁₋₁₀branched alkyl, or C₃₋₁₀ cyclic or bicyclic alkyl;

A is selected from the group consisting of: ##STR4## wherein: R₃ ishydrogen, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₆ alkylamino, C₂₋₁₂ dialkylamino, C₁₋₆alkylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms,nitro, cyano, carboxyl;

or, A is a substituted phenyl group of the following formula: ##STR5##wherein: R₄ and R₅, independent from each other, are selected from thefollowing: cyano, nitro, amino, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆alkoxy, C₁₋₆ perfluoroalkoxy, amino, C₁₋₆ alkylamino, C₂₋₁₂dialkylamino, sulfamyl, C₁₋₆ alkylsulfonamido, C₆₋₁₂ arylsulfonamido,alkylcarboxamido containing 2 to 7 carbon atoms, arylcarboxamidocontaining 7 to 13 carbon atoms, C₁₋₆ alkylsulfone, C₁₋₆perfluoroalkylsulfone, C₆₋₁₂ arylsulfone, chloro, bromo, fluoro, iodo,1-imidazolyl, carboxyl or hydrogen, with the proviso that R₄ and R₅cannot be hydrogen simultaneously;

or a pharmaceutically acceptable salt thereof.

A preferred aspect of this invention includes compounds of formula (I)wherein:

R₁ and R₂ are as stated above;

A is selected from the following: ##STR6## wherein: R₃ is as statedabove; or, A is a substituted phenyl group of the following formula:##STR7## wherein: R₄ and R₅, independent from each other, are selectedfrom the

following: cyano, nitro, amino, chloro, bromo, fluoro, iodo,1-imidazolyl, carboxyl or hydrogen, with the proviso that R₄ and R₅cannot be hydrogen simultaneously;

or a pharmaceutically acceptable salt thereof.

The most preferred aspect of this invention includes compounds offormula (I) wherein:

R₁ and R₂ are as stated above;

A is selected from the following: ##STR8## wherein: R₃ is as statedabove; or, A is a substituted phenyl group of the following formula:##STR9## wherein: R₄ and R₅, independent from each other, are selectedfrom the following: cyano, nitro, amino, chloro, bromo, fluoro, iodo,1-imidazolyl, carboxyl or hydrogen, with the proviso that R₄ and R₅cannot both be hydrogen simultaneously;

or a pharmaceutically acceptable salt thereof.

It is understood that the definition of the compounds of formula (I),when R₁, R₂, R₃, R₄ or R₅ contain asymmetric carbons, encompass allpossible stereoisomers and mixtures thereof which possess the activitydiscussed below. In particular, it encompasses racemic modifications andany optical isomers which possess the indicated activity. Opticalisomers may be obtained in pure form by standard separation techniques.The pharmaceutically acceptable salts are those derived from suchorganic and inorganic acids as: lactic, citric, acetic, tartaric,succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.Where R3, R4, or R5 is a carboxyl group, salts of the compounds of thisinvention may be formed with bases such as alkali metals (Na, K, Li) orthe alkaline earth metals (Ca or Mg).

The present invention also provides a process for the preparation of acompound of formula (I). More particularly, the compounds of formula (I)may be prepared by reacting a compound of formula (II): ##STR10##wherein X is a suitably designed .leaving group such as methoxy, ethoxy,isopropoxy, halogeno, or a similar leaving group, with a compound offormula (III):

    A.sub.1 --NH.sub.2                                         (III)

wherein A₁ is A, as defined hereinbefore or a group of atoms convertiblethereto, followed by treatment with a compound of formula (IV):##STR11## wherein R_(a1) and R_(a2) are R₁ and R₂, respectively, asdefined hereinbefore or a group of atoms convertible thereto in asolvent such as ethanol or methanol at elevated temperatures.

As mentioned previously, the compounds of formula (I) have been found torelax smooth muscle. They are therefore useful in the treatment ofdisorders associated with smooth muscle contraction, disorders involvingexcessive smooth muscle contraction of the urinary tract (such asincontinence), or of the gastrointestinal tract (such as irritable bowelsyndrome), asthma, and hair loss. Furthermore, the compounds of formula(I) are active as potassium channel activators which render them usefulfor treatment of peripheral vascular disease, hypertension, congestiveheart failure, stroke, anxiety, cerebral anoxia and otherneurodegenerative disorders.

The present invention accordingly provides a pharmaceutical compositionwhich comprises a compound of this invention and a pharmaceuticallyacceptable carrier. In particular, the present invention provides apharmaceutical composition which comprises an effective amount of acompound of this invention and a pharmaceutically acceptable carrier.

The compositions are preferably adapted for oral administration.However, they may be adapted for other modes of administration, forexample parenteral administration for patients suffering from heartfailure.

In order to obtain consistency of administration, it is preferred that acomposition of the invention is in the form of a unit dose. Suitableunit dose forms include tablets, capsules and powders in sachets orvials. Such unit dose forms may contain from 0.1 to 100 mg of a compoundof the invention and preferably from 2 to 50 mg. Still further preferredunit dosage forms contain 5 to 25 mg of a compound of the presentinvention. The compounds of the present invention can be administeredorally at a dose range of about 0.01 to 100 mg/kg or preferably at adose range of 0.1 to 10 mg/kg. Such compositions may be administeredfrom 1 to 6 times a day, more usually from 1 to 4 times a day.

The compositions of the invention may be formulated with conventionalexcipients, such as a filler, a disintegrating agent, a binder, alubricant, a flavoring agent and the like. They are formulated inconventional manner, for example, in a manner similar to that used forknown antihypertensive agents, diuretics and β-blocking agents.

The present invention further provides a compound of the invention foruse as an active therapeutic substance. Compounds of formula (I) are ofparticular use in the induction of smooth muscle relaxation.

The present invention further provides a method of treating smoothmuscle disorders in mammals including man, which comprises administeringto the afflicted mammal an effective amount of a compound or apharmaceutical composition of the invention.

The following examples are presented to illustrate rather than limit themethods for production of representative compounds of the invention.

EXAMPLE 13-(Pyridin-4-ylamino)-4-(1.2.2-trimethyl-propylamino)-cyclobut-3-ene-1.2-dione

Step 1) Preparation of3-(pyridin-4-ylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4mmol) in absolute ethanol (100 mL) was added a suspension of4-aminopyridine (2.77 g, 29.4 mmol) in ethanol (50 mL). The reactionmixture was refluxed for 4 hours then concentrated to give crudeproduct. Chromatography (EtOAc) afforded 0.632 g (10%) of a white solid:mp 120°-125° C.

Step 2) Preparation of3-(pyridin-4-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione

To the above squarate (0.332 g, 1.52 mmol) in acetonitrile (30 mL) wasadded 2-amino-3,3-dimethylbutane (0.200 ml, 1.52 mmol). A precipitateformed while stirring overnight. The crude reaction mixture was vacuumfiltered and the precipitate was dried in vacuo to yield 0.328 g (79%)of a pale yellow solid: mp 255°-257° C.; ¹ H NMR (DMSO-d₆): δ9.80 (s,1H), 8.42 (dd, 2H), 7.72 (d, 1H), 7.45 (dd, 2H), 3.96-4.00 (m, 1H), 1.18(s, 3H), 0.91 (s, 9H). IR (KBr): 3200, 1800, 1675, 1600 cm⁻¹ ; MS (m/z)274 (MH⁺).

Elemental analysis for C₁₅ H₁₉ N₃ O₂ Calc'd: C, 65.91; H, 7.01; N, 15.37Found: C, 65.91; H, 6.96; N, 15.22

EXAMPLE 2(Exo)-3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1.2-dione

To the product of Example 1, Step 1 (0.332 g, 1.52 mmol) in acetonitrile(30 mL) was added (±) exo-2-aminonorbornane (0.180 mL, 1.52 mmol). Aprecipitate forms while stirring overnight. The reaction mixture wasvacuum filtered and the precipitate was dried in vacuo to yield 0.350g(81%) of a pale yellow solid: mp 268°-270° C. (dec); ¹ H NMR (DMSO-d₆):δ9.70 (s, 1H), 8.40 (d, 2H), 7.74 (d, 1H), 7.42 (d, 2H), 3.90-3.95 (m,1H), 2.23-2.31 (m, 2H), 1.78-1.84 (m, 1H), 1.09-1.54 (m, 7H). IR (KBr):3200, 1795, 1670, 1600 cm⁻¹ ; MS (m/z) 283 (M⁺).

Elemental analysis for C₁₆ H₁₇ N₃ O₂ Calc'd: C, 67.83; H, 6.05; N, 14.83Found: C, 67.48; H, 6.03; N, 14.66

EXAMPLE 33-(Pyridin-3-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione

Step 1) Preparation of3-(pyridin-3-ylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4mmol) in absolute ethanol (100mL) was added a suspension of3-aminopyridine (2.77 g, 29.4 mmol) in ethanol (50 mL). The mixture washeated at reflux for 18 hours, then concentrated. Chromatography (4:1EtOAc/hexane) afforded 3.15 g (49%) of a white solid: mp 140°-145° C.

Step 2) Preparation of3-(pyridin-3-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2dione

To the above squarate (0.328 g, 1.50 mmol) in acetonitrile (30 mL) wasadded 2-amino-3,3-dimethylbutane (0.200 mL, 1.52 mmol). A precipitateforms while stirring overnight. The crude reaction mixture was vacuumfiltered and the precipitate was dried in vacuo to yield 0.27 g (66%) ofa white solid: mp 243°-245° C.; ¹ H NMR (DMSO-d₆): δ9.67 (s, 1H), 8.58(d, 1H),7.98 (d, 1H), 7.66 (d, 1H), 7.38 (m, 1H), 3.96-4.00 (m, 1H),1.18 (s, 3H), 0.95 (s, 9H); IR (KBr): 3200, 1800, 1665, 1600 cm⁻¹. MS(m/z) 273 (M⁺).

Elemental analysis for C₁₅ H₁₉ N₃ O₂ Calc'd: C, 65.91; H, 7.01; N, 15.37Found: C, 65.92; H, 6.95; N, 15.24

EXAMPLE 43-(2-Methylethylamino)-4-(pyridin-3-ylamino)(cyclobut-3-ene-1,2-dione

To the product from Example 3, Step 1 (0.180 g, 0.825 mmol) inacetonitrile (100 mL) was added isopropylamine (20 mL, 235 mmol). Thereaction was stirred at room temperature overnight, then concentrated.Trituration with ethylacetate/diethylether afforded 0.135 g (71%) of awhite solid: mp 258°-260° C.; ¹ H NMR (DMSO-d₆): δ9.62 (br s, 1H), 8.55(s, 1H), 8.22 (d, 1H), 7.94 (br d, 1H), 7.73 (br s, 1H), 7.36 (dd, 1H),4.20 (br m, 1H), 1.25 (d, 6H). IR (KBr): 3200, 1800, 1660, 1610, cm⁻¹ ;MS (m/z) 231(M⁺). Elemental analysis for C₁₂ H₁₃ N₃ O₂ Calc'd: C, 62.32;H, 5.66; N, 18.17 Found: C, 62.86; H, 5.79; N, 18.53

EXAMPLE 5 3-Dimethylamino-4-(pyridin-3-ylamino)-cyclobut-3-ene-1.2-dione

To the product from Example 3, Step 1 (0.330 g, 1.51 mmol) inacetonitrile (200 mL) was introduced to a stream of dimethylamine gas(15 minutes). The resultant solution was stirred overnight at roomtemperature, concentrated, and triturated withdichloromethane/diethylether to afford 0.278 g (85%) of an white solid:mp 235°-237° C.; ¹ H NMR (DMSO-d₆): δ9.50 (s, 1H), 8.46 (s, 1H), 8.22(d, 1H), 7.60 (d, 1H), 7.32 (dd, 1H). IR (KBr): 1790, 1685, 1600 cm⁻¹ ;MS (m/z) 217 (M⁺).

Elemental analysis for C₁₁ H₁₁ N₃ O₂ Calc'd: C, 60.82; H, 5.10; N, 19.34Found: C, 60.71; H, 5.07; N, 19.46

EXAMPLE 6 3-Amino-4-(pyridin-3-ylamino)-cyclobut-3-ene-1.2-dione

To the product from Example 3, Step 1 (0.330 g, 1.51 mmol) inacetonitrile (200 mL) was introduced to a stream of ammonia gas untilsolution became turbid. The resultant mixture was stirred overnight atroom temperature. The precipitate was vacuum filtered and dried toafford 0.266 g (93%) of a white solid: mp 297° C.(dec); ¹ H NMR(DMSO-d₆): δ8.56 (s, 1H), 8.22 (d, 1H), 7.92 (d, 1H), 7.37 (m, 1H). IR(KBr): 3200, 1800, 1670, 1625 cm⁻¹ ; MS (m/z) 189 (M⁺).

Elemental analysis for C₉ H₇ N₃ O₂ Calc'd: C, 57.14; H, 3.73; N, 22.21Found: C, 57.18; H, 3.69; N, 22.10

EXAMPLE 73-Tert-butylamino-4-(pyridin-3-ylamino)-cyclobut-3-ene-1,2-dione

The product from Example 3, Step 1 (2.60 g, 11.9 mmol) was dissolved intert-butylamine (50 mL). The solution was refluxed for three hours,cooled, and concentrated in vacuo. Trituration with diethyletherafforded 1.05 g (36%) of a white solid: mp 250°-252° C.; 1H NMR(DMSO-d₆): δ8.57 (s, 1H), 8.23 (d, 1H), 7.96 (d, 1H), 7.37 (m, 1H) 1.43(s,9H). IR (KBr): 1790, 1685, 1600 cm⁻¹ ; MS (m/z) 245 (M⁺).

Elemental analysis for C₁₃ H₁₅ N₃ O₂ Calc'd: .C, 63.66; H, 6.16; N,17.13 Found: C, 63.28; H, 6.22; N, 17.07

EXAMPLE 83-Tert-butylamino-4-(isoquinolin-5-ylamino)-cyclobut-3-ene-1,2-dione

Step 1) Preparation of3-(isoquinolin-5-ylamino)-4-ethoxy-cyclobut-3ene-1,2-dione

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4mmol) in absolute ethanol (100 mL) was added a suspension of5-aminoisoquinoline (4.24 g, 29.4 mmol) in ethanol (50 mL). The mixturewas heated to reflux overnight and then filtered to yield 2.30 g (29%)of solid: mp 182(dec) °C.

Step 2) Preparation of3-Tert-butylamino-4-(isoquinolin-5-ylamino)-cyclobut-3-ene-1,2-dioneone-eighth hydrate

The above squarate (0.300 g, 1.12 mmol) was dissolved in tert-butylamine(50 mL) and refluxed for three hours. The mixture was cooled,concentrated, and triturated with diethylether to afford 0.120 g (39%)of the title compound as a white solid, one-eighth hydrate: mp 268°-270°C.(dec); ¹ H NMR (DMSO-d₆): δ9.75 (s, 1H), 9.35 (s, 1H), 8.62 (d, 1H),8.19 (s, 1H), 8.01 (d, 1H), 7.88 (d, 1H), 7.68 (t, 1H), 1.47 (s, 9H). IR(KBr): 3200, 1785, 1670, 1600 cm⁻¹ ; MS (m/z) 295 (M⁺).

Elemental analysis for C₁₇ H₁₇ N₃ O₂. 0.125 (H₂ O) Calc'd: .C, 68.61; H,5.84; N, 14.12 Found: C, 68.08; H, 5.78; N, 13.75

EXAMPLE 9 3-Amino-4-(isoquinolin-5-ylamino)-Cyclobut-3-ene-1,2-dione

A suspension of the product from Example 8, Step 1 (0.190 g, 0.700 mmol)in ethanol (3.5 mL) was saturated with ammonia, capped, and heated to45° C. for three hours. The mixture was cooled, concentrated, andtriturated with diethylether. Crude product was recrystallized fromdimethylformamide/water to give 0.129 g (77%) of the title compound as apale yellow solid, one-eighth hydrate: mp 215° C.; ¹ H NMR (DMSO-d₆):δ9.87 (s, 1H), 9.34 (s, 1H), 8.60 (d, 1H), 7.40-8.6 (broad signal, NH2),8.02 (d, 1H), 7.86 (d, 1H), 7.77 (d, 1H), 7.68 (t, 1H). IR (KBr): 3200,1800, 1690, 1650 cm⁻¹ ; MS (m/z) 240(MH+).

Elemental analysis for C₁₃ H₉ N₃ O₂. 0.125 (H₂ O) Calc'd: C, 64.66; H,3.86; N, 17.40 Found: C, 64.10; H, 3.74; N, 16.99

EXAMPLE 103-(Quinolin-8-ylamino)-4-(1,2,2-trimethyl-propylamino)-Cyclobut-3-ene-1,2-dione

Step 1) Preparation of3-(quinolin-8-ylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione

To a solution of 8-aminoquinoline (1.00 g, 6.94 mmol) in ethanol (20 mL)was added 3,4-diethoxy-3-cyclobutene-1,2-dione (1.03 mL, 6.94 mmol) andthe resulting mixture was heated to reflux for 24 hours. The mixture wascooled, diluted with ethanol, and filtered. The crude product wastriturated with chloroform/hexanes, then purified by chromatography(EtOAc/hexane) to give 1.31 g (70%) of product: 1H NMR (DMSO-d₆) δ9.75(br m, 1H), 8.86 (dd, 1H), 8.26 (br m, 1H), 8.20 (dd, 1H), 7.57 (m, 2H),7.53 (dd, 1H), 4.95 (q, 2H), 1.59 (t, 3H).

Step 2) Preparation of3-(quinolin-8-ylamino)-4-(1,2,2-trimethylpropylamino)-cyclobut-3-ene-1,2-dione

To the above squarate (0.300 g, 1.12 mmol) in ethanol (5 mL) was added2-amino-3,3-dimethylbutane (0.18 mL, 1.34 mmol) and the resultingmixture was heated at 45° C. overnight, diluted with hexanes, andfiltered to give 0.294 g (81%) of a yellow solid: mp 244-245; ¹ H NMR(DMSO-d₆) δ10.45 (s, 1H), 8.97 (dd, 1H), 8.62 (d, 1H), 8.41 (dd, 1H),8.29 (dd, 1H), 7.6 (m, 3H), 4.10 (m, 1H), 1.21 (d, 3H), 0.94(s, 9H).IR(KBr):3280,2960,1790,1670cm⁻¹ ; MS (m/z)323(MH⁺).

Elemental analysis for C₁₉ H₂₁ N₃ O₂ Calc'd: C, 70.56; H, 6.54; N, 12.99Found: C, 70.38; H, 6.51; N, 12.94

EXAMPLE 11 3-Methylamino-4-(quinolin-8-ylamino)-cyclobut-3-ene-1,2-dione

To the product from Example 10, Step 1 (0.64 g, 2.38 mmol) was addedethanolic methylamine (8.03M, 13 mL) and the mixture was stirred at 25°C. for 6 hours. Diethyl ether was added, and the resulting solid wasfiltered and washed with additional ether. Chromatography(EtOAc/hexanes) followed by trituration with dimethylsulfoxide/waterafforded 0.398 g (66%) of product as a yellow solid: mp 236°-237° C.; ¹H NMR (DMSO-d₆) δ10.32 (s, 1H), 8.95 (dd, 1H), 8.63 (m, 1H), 8.40 (dd,1H), 8.26 (d, 1H), 7.68-7.54 (m, 3H), 3.27 (d, 3H). IR (KBr) 3200, 1795,1610 cm⁻¹ ; MS (m/z) 253 (M⁺), 155 (100%).

Elemental analysis for C₁₄ H₁₁ N₃ O₂ Calc'd: C, 66.39; H, 4.38; N, 16.59Found: C, 66.13; H, 4.43; N, 16.48

EXAMPLE 12 3-Amino-4-(quinolin-8-ylamino)-cyclobut-3-ene-1,2-dione

Ammonia gas was bubbled through a slurry of the product from Example 10,Step 1 (0.640 g, 2.38 mmol) in ethanol (13 mL) at -35° C. After 6 hours,the mixture was diluted with diethylether and filtered. Chromatography(EtOAc/hexanes) followed by trituration with dimethylsulfoxide/waterafforded 0.342 g (60%) of product as a yellow solid, quarter hydrate: mp263° C. (dec); ¹ H NMR (DMSO-d₆) δ10.35 (s, 1H), 8.95 (dd, 1H), 8.45 (brs, 2H), 8.40 (dd, 1H), 8.28 (dd, 1H), 7.66-7.55 (m, 3H). IR (KBr) 3260,1800 cm⁻¹ ; MS (m/z) 239 (M⁺), 211, 183, 155, 129 (100%).

Elemental analysis for C₁₃ H₉ N₃ O₂. 0.25 (H₂ O) Calc'd: C, 64.06; H,3.72; N, 17.24 Found: C, 63.28; H, 3.85; N, 16.99

EXAMPLE 13 3-(Quinolin-3-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione

Step 1) Preparation of3-(Quinolin-3-ylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione

To a solution of 3-aminoquinoline (2.12 g, 14.69 mmol) in ethanol (60mL) was added 3,4-diethoxy-3-cyclobutene-1,2-dione (2.50 g, 14.69 mmol)and the resulting mixture was heated to reflux for 24 hours. The mixturewas cooled, filtered, and the product was washed with diethylether anddried in vacuo to give 3.14 g (80%) of yellow solid which was usedwithout purification: ¹ H NMR (DMSO-d₆) δ11.14 (s, 1H), 8.92 (dd, 1H),8.20 (dd, 1H), 7.90 (m, 2H), 7.63 (m, 2H).

Step 2) Preparation of3-(Quinolin-3-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione

To the above squarate (0.30 g, 1.12 mmol) in ethanol (8 mL) was added2-amino-3,3-dimethylbutane (0.18 mL, 1.34 mmol) and the resultingmixture was heated at 50° C. overnight. The precipitate was filtered,washed with diethylether, and dried in vacuo to afford 0.30 g (83%) ofproduct as a light tan solid: mp 242°-246° C.; ¹ H NMR (DMSO-d₆) δ9.93(s, 1H), 8.90 (d, 1H), 8.38 (br s, 1H), 7.97 (d, 1H), 7.84 (dd, 1H),7.75-7.55 (m, 2H), 4.00 (m, 1H), 1.20 (d, 3H), 0.94 (s, 9H). IR (KBr)3160, 2960, 1795, 1650 cm⁻¹ ; MS (m/z) 324 (MH⁺).

Elemental analysis for C₁₉ H₂₁ N₃ O₂ Calc'd: C, 70.57; H, 6.55; N, 12.99Found: C, 70.97; H, 6.41; N, 13.04

EXAMPLE 143-Tert-butylamino-4-(quinolin-3-ylamino)-cyclobut-3-ene-1,2-dione

To the product from Example 13, Step 1 (0.30 g, 1.12 mmol) in ethanol (8mL) was added tert-butylamine (0.35 mL, 3.36 mmol) and the resultingmixture was heated at 60° C. overnight. The mixture was concentrated,and the residue was dissolved in ethylacetate. Addition of hexanesinduced precipitation of product which was filtered and triturated withdiethylether/hexanes. Filtration and drying afforded 0.28 g (85%) of thetitle compound as a yellow solid, three-quarter hydrate: mp 257°-260°C.; ¹ H NMR (DMSO-d₆) d 10.00 (br d, 1H), 8.9 (d, 1H), 8.4 (m, 1H), 8.02(d, 1H), 7.96 (br d, 1H), 7.86 (dd, 1H), 7.66-7.54 (m, 2H), 1.45 (s,9H). IR (KBr) 3400, 3200, 2980, 1785, 1680 cm⁻¹ ; MS (m/z) 296 (MH⁺).

Elemental analysis for C₁₇ H₁₇ N₃ O₂. 0.75 (H₂ O) Calc'd: C, 66.11; H,6.04; N, 13.61 Found: C, 66.08; H, 5.86; N, 13.36

Example 153-(Quinolin-3-ylamino)-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione

To the product from Example 13, Step 1 (0.30 g, 1.12 mmol) in ethanol (7mL) was added tert-amylamine (0.39 mL, 3.35 mmol). After 48 hours ofstirring at 45° C., an additional aliquot of amine (0.39 mL) was added.After 3 hours, the mixture was concentrated and the residue wastriturated with hexane/diethylether to give 0.328 g (95%) of product asan off white solid, three-quarter hydrate: mp 234°-236° C.; 1H NMR(DMSO-d₆) δ10.04 (br s, 1H), 8.9 (d, 1H), 8.4 (d, 1H), 7.95 (d, 1H),7.86, (m, 2H), 7.6 (m, 2H), 1.78 (q, 2H), 1.40 (s, 6H), 0.89 (t, 3H). IR(KBr) 3370, 3240, 2960, 1785, 1680 cm⁻¹ ; MS (m/z) 309 (M⁺).

Elemental analysis for C₁₈ H₁₉ N₃ O₂. 0.75 (H₂ O) Calc'd: C, 66.96; H,6.40; N, 13.01 Found: C, 67.11; H, 6.26; N, 13.05

EXAMPLE 163-(6-Methoxy-quinolin-8-ylamino)-4-(1,2,2-trimethyl-propylamino)-Cyclobut-3-ene-1,2-dione

Step 1) Preparation of3-(6-Methoxy-quinolin-8-ylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione

In a procedure identical to Example 10, Step 1,8-amino-6-methoxyquinoline (2.00 g, 11.48 mmol) was reacted with3,4-diethoxy-3-cyclobutene-1,2-dione (1.70 mL, 11.48 mmol) to give 0.99g (29%) of product: ¹ H NMR (DMSO-d₆) δ10.21 (s, 1H), 8.75 (dd, 1H),8.29 (dd, 1H), 7.61 (m, 2H), 7.17 (d, 1H), 4.76 (q, 2H), 3.90 (s, 3H),1.40 (t, 3H).

Step 2) Preparation of3-(6-Methoxy-quinolin-8-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione

In a procedure identical to Example 10, Step 2, the above squarate (0.25g, 0.839 mmol) and 2-amino-3,3-dimethylbutane (0.13 mL, 1.01 mmol) werereacted to give 0.21 g (71%) of title compound as an off-white solid: mp243°-245° C.; ¹ H NMR (DMSO-d₆) δ10.43 (br s, 1H), 8.78 (dd, 1H), 8.64(d, 1H), 8.28 (dd, 1H), 8.13 (d, 1H), 7.56 (dd, 1H), 7.02 (d, 1H), 4.11(m, 1H), 3.88 (s, 3H), 1.20 (d, 3H), 0.94 (s, 9H). IR (KBr) 3400, 3220,2950, 1780cm⁻¹ ; MS (m/z) 353 (M⁺).

Elemental analysis for C₂₀ H₂₃ N₃ O₃ Calc'd: C, 67.96; H, 6.55; N, 11.88Found: C, 67.72; H, 6.56; N, 11.74

EXAMPLE 173-(6-Methoxy-quinolin-8-ylamino)-4-methylamino-cyclobut-3-ene-1,2-dione

The product from Example 16, Step 1 (0.25 g, 0.839 mmol) was added to 8Nethanolic methylamine (7 mL). The resulting mixture was stirred for 4hours and filtered. The solid was recrystallized fromdimethylsulfoxide/water to give 0.12 g (50%) of product as a yellowsolid: mp >275° C.; 1H NMR (DMSO-d₆) δ10.29 (br s, 1H), 8.75 (dd, 1H),8.68 (br q, 1H), 8.27 (dd, 1H), 8.10 (d, 1H), 7.55 (m, 1H), 7.00 (d,1H), 3.88 (s, 3H), 3.26 (d, 3H). IR (KBr) 3240, 1795 cm⁻¹ ; MS (m/z) 283(M⁺), 185 (100%).

Elemental analysis for C₁₅ H₁₃ N₃ O₃ Calc'd: C, 63.59; H, 4.62; N, 14.83Found: C, 63.30; H, 4.58; N, 14.70

EXAMPLE 183-Tert-butylamino-4-(quinolin-6-ylamino)-cyclobut-3-ene-1,2-dione

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4mmol) in absolute ethanol (100 mL) was added a suspension of6-aminoquinoline (4.24 g, 29.4 mmol) in ethanol (50 mL). The mixture washeated at reflux for 18 hours, cooled, and vacuum filtered to afford6.64 g (84%) of crude product (mp: 185-187, dec) which was used withoutfurther purification. An aliquot (3.00 g, 11.2 mmol) was dissolved intert-butylamine (50 mL). The solution was refluxed for three hours,cooled, and concentrated. The residue was recrystallized twice fromethanol then triturated with diethylether to give 1.05 g (31% ) of therifle compound as a pale yellow solid, one-quarter hydrate: mp 234°-236°C.; ¹ H NMR (DMSO-d₆): δ9.92 (s, 1H), 8.76 (d, 1H), 8.24 (d, 1H), 8.01(d, 1H), 7.98 (s, 1H), 7.97 (d, 1H), 7.88 (d,1H), 7.48 (m, 1H), 1.45 (s,9H). IR (KBr): 1780, 1665, 1610 cm⁻¹ ; MS (m/z) 295 (M⁺).

Elemental analysis for C₁₇ H₁₇ N₃ O₂. 0.25 (H₂ O) Calc'd: C, 68.10; H,5.88; N, 14.01 Found: C, 67.63; H, 5.92; N, 13.96

EXAMPLE 193-Tert-butylamino-4-(1H-indazol-6-ylamino)-cyclobut-3-ene-1,2-dione

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (4.5 1 g, 26.5mmol) in absolute ethanol (100 mL) was added a suspension of6-aminoindazole (3.53 g, 29.4 mmol) in ethanol (50 mL). The mixture wasrefluxed for 18 hours, cooled, and vacuum filtered to afford 3.60 g(53%) of crude product which was used without further purification. Analiquot (2.00 g, 7.77 mmol) was dissolved in tert-butylamine (50 mL) andthe resulting mixture was refluxed for three hours, cooled, andconcentrated. The crude product was recrystallized from ethanol/water togive 0.45 g (19%) of the title compound as a white solid, dihydrate: mp183°-185° C.; ¹ H NMR (DMSO-d₆): δ13.00 (s, 1H), 9.74 (s, 1H), 7.97 (s,1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.70 (d, 1H), 7.05 (d, 1 H), 1.44 (s,9H). IR (KBr): 3200, 1790, 1655, 1600 cm⁻¹ ; MS (m/z) 284 (M⁺).

Elemental analysis for C₁₅ H₁₆ N₄ O₂. 2 (H₂₀) Calc'd: C, 56.24; H, 6.29;N, 17.49 Found: C, 56.06; H, 6.29; N, 17.43

EXAMPLE 203-(Isoquinolin-5-ylamino)-4-methylamino-cyclobut-3-ene-1,2-dione

To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4mmol) in absolute ethanol (100 mL) was added a suspension of5-aminoisoquinoline (4.24 g, 29.4 mmol) in ethanol (50 mL). The mixturewas heated at reflux for 18 hours, cooled, and vacuum filtered to afford2.30 g (29%) of crude product (mp: 182, dec) which was used withoutfurther purification. To an aliquot (0.335 g, 1.25 mmol) of the squaratein ethanol (1.5 mL) was added 33% methylamine in ethanol (1.4 mL). Themixture was heated to 40° C. for 15 minutes, cooled, and concentrated.Trituration with diethylether afforded crude product which wascrystallized from a minimal amount of methanol to give 0.149 g (47%) ofan pale yellow solid: mp 245°-250° C. (dec); ¹ H NMR (DMSO-d₆): δ9.79(s, 1H), 9.33 (s, 1H), 8.60 (d, 1H), 7.99 (d, 1H), 7.86 (d, 1H), 7.76(br d, 1H), 7.66 (t, 1H), 7.76 (br s, 1H). IR (KBr): 3200, 1800, 1680,1605 cm⁻¹ ; MS (m/z) 253 (M⁺).

Elemental analysis for C₁₄ H₁₁ N₃ O₂ Calc'd: C, 66.40; H, 4.38; N, 16.59Found: C, 66.06; H, 4.35; N, 16.32

EXAMPLE 214-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylaminol]-benzonitrile

Step 1) Preparation of4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile

4-Aminobenzonitrile (3.47 g, 29.4 mmol) was added to a solution of3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absoluteethanol (100 mL). The mixture was heated at reflux overnight. Themixture was cooled, and the resulting yellow precipitate was collectedby vacuum filtration. Yield: 2.60 g (37%): mp 218°-222° C.

Step 2) Preparation of4-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-benzonitrile

To the above squarate (1.00 g, 4.13 mmol) in acetonitrile (250 mL) wasadded 2-amino-3,3-dimethylbutane (0.600 mL, 4.48 mmol). A precipitateforms while stirring overnight. The crude reaction mixture is vacuumfiltered. The solid is triturated with diethylether to afford 0.620 g(50%) of product as a yellow solid: mp 241°-243° C.; ¹ H NMR (DMSO-d₆):δ9.89 (s, 1H), 7.78 (d, 2H), 7.72 (d, 1H), 7.60 (d, 2H), 3.95-4.00 (m,1H), 1.18 (d, 3H), 0.91 (s, 9H). IR (KBr): 3200, 1790, 1660, 1600 cm⁻¹ ;MS (m/z) 297 (M⁺).

Elemental analysis for C₁₇ H₁₉ N₃ O₂ Calc'd: C, 68.67; H, 6.44; N, 14.13Found: C, 68.63; H, 6.15; N, 14.30

EXAMPLE 22(Exo)-4-[2-(bicyclo[2,2,1]hept-2-ylamino)-3,4-dioxo-cyclobut-1-enylamino1-benzonitrile

To the product of Example 21, Step 1 (0.368 g, 1.52 mmol) inacetonitrile (30 mL) was added (±)exo-2-aminonorbornane (0.180 mL, 1.52mmol). A precipitate forms while stirring overnight. The crude reactionmixture was vacuum filtered and triturated with diethylether to afford0.370 g (79%) of a yellow solid: mp 288-290° C. ;¹ H NMR (DMSO-d₆):δ9.79 (s, 1H), 7.78 (d, 2H), 7.76 (m, 1H), 7.58 (d, 2H), 3.90-3.98 (m,1H), 2.22-2.34 (m, 2H), 1.76-1.86 (m, 1H), 1.08-1.56 (m, 7H). IR (KBr):2220, 1790, 1650, 1600 cm⁻¹ ; MS (m/z) 307 (M⁺).

Elemental analysis for C₁₈ H₁₇ N₃ O₂ Calc'd: C, 70.34; H, 5.57; N, 13.67Found: C, 70.17; H, 5.50; N, 13.96

EXAMPLE 234-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino1-benzenesulfonamide

To a slurry of sulfanilamido (1.72 g, 10.0 mmol) in ethanol (10 mL) wasadded 3,4-diethoxy-3-cyclobutene-1,2-dione (2.43 g, 14.3 mmol). Thereaction was heated at reflux overnight, cooled, and a yellowprecipitate was collected by vacuum filtration. Yield: 2.60 g.(98%): mp210°-212° C.

To the above squarate (0.750 g, 2.84 mmol) in ethanol (10 mL) was added2-amino-3,3-dimethylbutane (0.380 mL, 2.84 mmol). The mixture was heatedto reflux overnight then concentrated. The residue was dissolved inacetone/ethylacetate (1:1 ) and filtered through a plug of silica gel toafford 0.200 g (20%) of the title compound as a white solid,hemi-hydrate: mp 233°-235° C.; ¹ H NMR (DMSO-d₆): δ9.87 (s, 1H), 7.79(d, 2H), 7.75 (d, 1H), 7.58 (d, 2H), 7.25 (s, 2H), 4.00 (m, 1H), (d,3H), 0.92 (s, 9H). IR (KBr): 1790, 1670, 1600 cm⁻¹ ; MS (m/z) 351 (M⁺).

Elemental analysis for C₁₆ H₂₁ N₃ O₄ S . 1/2 H₂ O

Calc'd: C, 53.32; H, 6.15; N, 11.66

Found: C, 52.89; H, 5.81; N, 11.42

The smooth muscle relaxing activity of the compounds of this inventionwas established in accordance with standard pharmaceutically acceptedtest procedures in representative compounds as follows:

Sprague-Dawley rats (150-200 g) are rendered unconscious by CO₂asphyxiation and then euthanized by cervical dislocation. The bladder isremoved into warm (37 deg. C.) physiological salt solution (PSS) of thefollowing composition (mM): NaCl, 118.4; KCl, 4.7; CaCl₂, 2.5; MgSO₄,4.7; H₂ O, 1.2; NaHCO₃, 24.9; KH₂ PO₄, 1.2; glucose, 11.1; EDTA, 0.023;gassed with 95% O₂ ; 2/5% CO₂ ; pH 7.4. The bladder is opened and thencut into strips 1-2 mm in width and 7-10 mm in length. The strips aresubsequently suspended in a 10 mL tissue bath under an initial restingtension of 1.5 g. The strips are held in place by two surgical clips oneof which is attached to a fixed hook while the other is attached to anisometric force transducer. The preparations, which usually exhibitsmall spontaneous contractions, are allowed to recover for a period of 1hour prior to a challenge with 0.1 uM carbachol. The carbachol is thenwashed out and the tissue allowed to relax to its resting level ofactivity. Following one further 30 minute period of recovery, anadditional 15 mM KCl are introduced into the tissue bath. This increasein KCl concentration results in a large increase in the amplitude ofspontaneous contractions (and initiation of contractions in previouslyquiescent strips) superimposed upon a small increase in basal tone.Following stabilization of this enhanced level of contractile activity,incremental increases in the concentration of test compound or vehicleare introduced into the tissue bath. Contractile activity is measuredfor each compound or vehicle concentration during the last minute of a30 minute challenge.

The isometric force developed by the bladder strips is measured using aconcentration required to elicit 50% inhibition of pre-drug contractileactivity (IC₅₀ concentration) is calculated from thisconcentration-response curve. The maximum percentage inhibition ofcontractile activity evoked by a test compound is also recorded forconcentrations of test compound less than or equal to 30 μM.

The results of this study are shown in Table I.

                  TABLE I                                                         ______________________________________                                        Inhibition of Contractions in Isolated Rat Bladder Strips                             no. of               Inhibition of Force                              Compound                                                                              animals    IC.sub.50 (%) at (x) μM                                 ______________________________________                                        Example 1                                                                             6          1.36 μM                                                                              --                                               Example 2                                                                             2          15.85 μM                                                                             --                                               Example 3                                                                             3          1.95 μM                                                                              --                                               Example 6                                                                             2          --        31% (30 μM)                                   Example 7                                                                             2          2.8 μM --                                               Example 8                                                                             4          1.84 μM                                                                              --                                               Example 9                                                                             4          --        43% (30 μM)                                   Example 10                                                                            4          8.0 μM --                                               Example 14                                                                            4          --        51% (30 μM)                                   Example 19                                                                            4          6.34 μM                                                                              --                                               Example 21                                                                            2          0.52 μM                                                                              --                                               ______________________________________                                    

Hence, the compounds of this invention have a pronounced effect onsmooth muscle contractility and are useful in the treatment of urinaryincontinence, irritable bladder and bowel disease, asthma, hypertension,stroke, and similar diseases as mentioned above, which are amenable totreatment with potassium channel activating compounds by administration,orally, parenterally, or by aspiration to a patient in need thereof.

What is claimed is:
 1. A compound of the formula: ##STR12## wherein: R₁and R₂ are, independent from each other, hydrogen, C₁₋₁₀ straight chainalkyl, C₁₋₁₀ branched chain alkyl or C₃₋₁₀ cyclic or bicyclic alkyl;A isselected from the group consisting of: ##STR13## wherein: R₃ ishydrogen, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, amino, C₁₋₆ alkylamino, C₂₋₁₂ dialkylamino, C₁₋₆alkylsulfonamido, alkylcarboxamido containing 2 to 7 carbon atoms,nitro, cyano or carboxyl;or a pharmaceutically acceptable salt thereof.2. A compound of claim 1 in which A is selected from the following:##STR14## wherein R₃ is hydrogen, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆alkoxy, C₁₋₆ perfluoroalkoxy, amino, C₁₋₆ alkylamino, C₂₋₁₂dialkylamino, C₁₋₆ alkylsulfonamido, alkylcarboxamido containing 2 to 7carbon atoms, nitro, cyano or carboxyl;or a pharmaceutically acceptablesalt thereof.
 3. A compound of claim 1 in which A is selected from thefollowing: ##STR15## wherein R₃ is hydrogen, C₁₋₆ alkyl, C₁₋₆perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆ perfluoroalkoxy, amino, C₁₋₆alkylamino, C₂₋₁₂ dialkylamino, C₁₋₆ alkylsulfonamido, alkylcarboxamidocontaining 2 to 7 carbon atoms, nitro, cyano or carboxyl;or apharmaceutically acceptable salt thereof.
 4. A compound of claim 1 whichis3-(quinolin-8-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dioneor a pharmaceutically acceptable salt thereof.
 5. A compound of claim 1which is 3-methylamino-4-(quinolin-8-ylamino)-cyclobut-3-ene-1,2-dioneor a pharmaceutically acceptable salt thereof.
 6. A compound of claim 1which is 3-amino-4-(quinolin-8-ylamino)-cyclobut-3-ene-1,2-dione or apharmaceutically acceptable salt thereof.
 7. A compound of claim 1 whichis3-(quinolin-3-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dioneor a pharmaceutically acceptable salt thereof.
 8. A compound of claim 1which is3-tert-butylamino-4-(quinolin-3-ylamino)-cyclobut-3-ene-1,2-dione or apharmaceutically acceptable salt thereof.
 9. A compound of claim 1 whichis3-(quinolin-3-ylamino)-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dioneor a pharmaceutically acceptable salt thereof.
 10. A compound of claim 1which is3-(6-methoxy-quinolin-8-ylamino)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dioneor a pharmaceutically acceptable salt thereof.
 11. A compound of claim 1which is3-(6-methoxy-quinolin-8-ylamino)-4-methylamino-cyclobut-3-ene-1,2-dioneor a pharmaceutically acceptable salt thereof.
 12. A compound of claim 1which is3-tert-butylamino-4-(quinolin-6-ylamino)-cyclobut-3-ene-1,2-dione or apharmaceutically acceptable salt thereof.
 13. A method for reducing theadverse effects of smooth muscle contractions which comprisesadministering, orally or parenterally, to a patient in need thereof, acompound of the formula: ##STR16## wherein: R₁ and R₂ are, independentfrom each other, hydrogen, C₁₋₁₀ straight chain alkyl, C₁₋₁₀ branchedalkyl, or C₃₋₁₀ cyclic or bicyclic alkyl;A is selected from the groupconsisting of: ##STR17## wherein: R₃ is hydrogen, C₁₋₆ alkyl, C₁₋₆perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆ perfluoroalkoxy, amino, C₁₋₆alkylamino, C₂₋₁₂ dialkylamino, C₁₋₆ alkylsulfonamido, alkylcarboxamidocontaining 2 to 7 carbon atoms, nitro, cyano or carboxyl;or apharmaceutically acceptable salt thereof.
 14. The method of claim 13 inwhich the smooth muscle adversely contracting causes urinaryincontinence.
 15. The method of claim 13 in which the smooth muscleadversely contracting causes irritable bowel syndrome.